Thinking critically about the Central Dogma of Molecular Biology

Our department is preparing to review our undergraduate courses and programs. Part of the review will be to examine our fundamental goals and objectives and determine if we are meeting them. In preparation for this exercise, I've been going over some papers that have been sitting around my office.

One of them concerns teaching the Central Dogma of Molecular Biology (Wright et al., 2014). It was just published last year. The authors have discovered that students have a "weak conceptual understanding" of information flow. Here's how they describe it in the abstract.

The central dogma of molecular biology, a model that has remained intact for decades, describes the transfer of genetic information from DNA to protein though an RNA intermediate. While recent work has illustrated many exceptions to the central dogma, it is still a common model used to describe and study the relationship between genes and protein products. We investigated understanding of central dogma concepts and found that students are not primed to think about information when presented with the canonical figure of the central dogma. We also uncovered conceptual errors in student interpretation of the meaning of the transcription arrow in the central dogma representation; 36% of students (n = 128; all undergraduate levels) described transcription as a chemical conversion of DNA into RNA or suggested that RNA existed before the process of transcription began. Interviews confirm that students with weak conceptual understanding of information flow find inappropriate meaning in the canonical representation of central dogma. Therefore, we suggest that use of this representation during instruction can be counterproductive unless educators are explicit about the underlying meaning.

This is a paper that interests me greatly because I think it's very important to focus on teaching important principles and concepts instead of trivial details.

Most of you know that I'm also interested in the Central Dogma [Basic Concepts: The Central Dogma of Molecular Biology]. I've been writing about it for almost two decades. There are two versions of the Central Dogma. The one you are most familiar with is the version promoted by Watson in 1965.

The discovery of reverse transcriptase a few years later prompted him to revise this version in subsequent editions so that now we often see double arrows going in both direction between DNA and RNA.

This is not the version that Francis Crick wrote about in 1958. He drew two diagrams illustrating all the possible directions of information transfer (left below) and the ones that may be permitted (right). The Central Dogma, according to Crick, is that "... once (sequential) information has passed into protein it cannot get out again."

Crick re-stated his original version in a classic Nature paper in 1970 after the discovery of reverse transcriptase. He pointed out that the synthesis of DNA from RNA is not a violation of the Central Dogma (original Crick version) because he explicitly mentioned that as a possibility. Furthermore, the Central Dogma says nothing about information flow between RNA and DNA it only forbids information flow from protein to nucleic acids.

He made this very clear in his 1970 paper.

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)

Crick's papers are all about information flow. They have very little to do with transcription, reverse transcription, and translation.

I think it's important for students to understand this concept and to understand that information can't flow back from protein to nucleic acids. I think it's important for them to understand that the common version of the Central Dogma (DNA to RNA to protein) is a misrepresentation of Crick's original ideas. Correcting this misunderstanding is a good way to reinforce the concept.

Let's look at what Wright et al. (2014) have to say about the Central Dogma of Molecular Biology.

Indeed, the concept of information being stored in DNA molecules, copied into RNA intermediates, and expressed in proteins that carry out cellular functions, is known as the "central dogma" of molecular biology. Francis Crick first described the central dogma as "the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid" (Crick, 1970). The canonical interpretation of the central dogma is that genetic information (DNA) is used to generate transient messenger molecules (RNA) that are themselves used to direct synthesis of particular protein products and that the proteins are responsible for most cellular functions.

I don't think the authors have read the 1970 Nature paper very carefully because they misrepresent the main point that Crick was making in that paper. The information flow diagrams that Crick published are what he refers to as the "Sequence Hypothesis." This is NOT the Central Dogma.

It's going to be difficult to test student's understanding of information flow if it's not taught correctly. The authors may be testing whether students understand transcription but that's an entirely different topic—one that should be covered in several lectures on the role of RNA polymerase in copying DNA.

The authors seem to recognize that the Watson version of the Central Dogma has some problems.

In a recent review "revisiting" the central dogma, Shapiro (2009) wrote, "The idea of a ‘dogma’ in science has always struck me as inherently self-contradictory. The scientific method is based upon continual challenges to accepted ideas and the recognition that new information inevitably leads to new conceptual formulations." The discoveries of reverse transcription, catalytically active RNA molecules, and posttranscriptional modification of RNA molecules are examples of a few of the many exceptions to the central dogma. And while the traditional representation of the central dogma (Figure 1) suggests a very simplistic mechanism for information flow, in reality, the processes that direct the synthesis of each macromolecule are numerous and complex. Most postsecondary educators would likely agree that concepts related to the central dogma are crucial to their curricula in courses such as those in introductory biology, cell and molecular biology, genetics, and developmental biology, as well as in many others. As the fields of genomics and bioinformatics continue to be revolutionized by advancing technologies such as whole-genome sequencing (Ng and Kirkness, 2010; Mavromatis et al., 2012), it is critically important that we prepare our biology students to think deeply and carefully about information flow.

I've posted a critique of Shapiro's article at:Revisiting the Central Dogma in the 21st Century. He's another scientist who quotes Crick's Nature paper without understanding it.

Here's the problem. While there is general agreement that we should be concentrating on teaching fundamental concepts, there's less agreement on what those concepts are. I've also noticed a disturbing trend in the pedagogical literature. Many teachers of biochemistry and molecular biology will advocate their version of fundamental concepts but far too often those concepts are flawed.

As Wright et al. put it, "As the fields of genomics and bioinformatics continue to be revolutionized by advancing technologies such as whole-genome sequencing, it is critically important that we prepare our biology students to think deeply and carefully about information flow." I'm sure we all agree with that sentiment.

They also seem to be aware of the fact that students will often begin a class with misconceptions and misunderstandings and good teachers will make an effort to correct those misunderstanding. They say ...

In Science Teaching Reconsidered: A Handbook, conceptual misunderstandings are described as phenomena that occur when students are not forced to confront the discrepancies between their own preconceived ideas and real-world observations. The failure to critically examine one's own mental models leads to weak, faulty models, with little confidence behind them. Conceptual misunderstandings are problematic, because their existence often interferes with learning new concepts, especially if the misconceptions seem rational and useful to the learner at the time ...

I don't think we are doing enough to alert teachers to the fact that they, themselves, might suffer from this problem. I agree with their conclusion ...

... it is crucial that we, as educators, are careful about our language with students and demand that students be equally precise. Without such rigor, we cannot evaluate their mental models or prevent the creation of new misconceptions.

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Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163 [PDF].

Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]

Watson, J.D. (1965) The Molecular Biology of the Gene. W.A. Benjamin. Inc. New York

Wright, L.K., Fisk, J.N., and Newman, D.L. (2014) DNA --> RNA: What Do Students Think the Arrow Means? CBE-Life Science Education 13:338-348. [doi: 10.1187/cbe.CBE-13-09-0188]